Congenital erythropoietic porphyria: two case reports.

Porphyrias form a group of disorders caused due to defects in the haem synthetic pathway. Congenital erythropoietic porphyia (CEP) is the rarest of the bullous porphyrias (less than 200 cases have been reported till recent times) and a clinician may not see a case during his professional life. We present two cases of CEP. One child with CEP presented with typical infancy-onset blistering, photosensitivity, red urine, and erythrodontia, with hypertrichosis of the upper arms and back. The other child of CEP presented with childhood-onset blistering, mutilation, and hypertrichosis on the face.

Introduction

Porphyrias form a group of disorders caused by enzymatic defects in the biosynthesis of haem. Haem is required for the synthesis of hemoglobin by erythrocyte precursors in the bone marrow and for the cytochrome P450 enzyme system in liver. The porphyrias are classified into three forms (on the basis of the predominant site of accumulation of metabolic intermediates): hepatic, erythrocytic, and hepatoerythrocytic. Congenital erythropoietic porphyria (also known as Gόnther disease), as the name implies, is an erythrocytic porphyria and it is inherited as an autosomal recessive disorder. Despite the limited treatments currently available, the prognosis is not invariably poor and most patients survive to adulthood. We present two cases of CEP with classical clinical presentations.

Case Report

Case 1

A 3-year-old male child, born of consanguineous marriage, presented with blisters on exposed areas since the age of around 6 months. The blisters used to heal with scars. Since early infancy the mother had noticed reddish colored urine. The child's mental and physical development had been normal. There was no family history of a similar problem. There was no history of acute attacks. On examination, the child's face was badly scarred. There was hypertrichosis on the shoulders, arms, and face [Figure 1]. The teeth were of coppery-red color [Figure 2]. There were a few intact blisters and crusted lesions on the hands [Figure 3] and feet [Figure 4]. Atrophic scars were also present on the extremities. On the basis of the history of blistering on the exposed areas since early infancy, healing with atrophic scarring, erythrodontia, and red-colored urine, we made a clinical diagnosis of CEP. Routine investigations were within normal limits except for mild anemia. The urine did not show increased level of porphobilinogen (PBG). Further investigations were not carried out. The child was treated symptomatically.

Figure 1

Hyperpigmentation of face with hypertrichosis on the forehead and temples

Figure 2

Erythrodontia

Figure 3

Blisters on the dorsum of the hands

Figure 4

Blisters on the feet

Case 2

A 13-year-old child, born of consanguineous marriage, presented with photosensitivity and recurrent blistering. The blisters were first noticed by the parents at the age of 4–5 years. The blisters were mostly present on exposed areas and used to heal with scarring. There was no history of a similar problem in the family. There was no history of acute neurological attacks. On examination, there were severe atrophic scars on the face and exposed parts of the extremities, which had resulted in mutilating deformities of the fingers. Hypertrichosis, pigmentation, and milia formation were also present on the face [Figure 5]. Though erythrodontia was not spotted with the naked eyes, the teeth revealed a pink-red fluorescence under Wood's lamp. Histopathological examination of an intact bulla revealed the subepidermal location of the blister [Figure 6].

Figure 5

Hypertrichosis, pigmentation, milia, and atrophic scars on the face and exposed parts, with mutilating deformities of the fingers

Figure 6

Photomicrograph showing subepidermal blister (H and E; 100×)

A clinical diagnosis of cutaneous porphyria was made on the basis of the severe photosensitivity, blistering, and hypertrichosis. The early onset and the mutilation of the fingers were highly suggestive of CEP. The patient was investigated. Routine investigations, including liver and renal function tests, were within normal limits except for mild anemia (Hb 8.0 g/dl, reticulocyte count 7% of circulating erythrocytes). ELISA for HIV was negative. PBG was normal in urine. On screening with a spectrophotometer, urinary total porphyrin was 1187 nmol/mmol of creatinine (normal <35 nmol/mmol). Twenty-four-hour urinary levels of uroporphyrin and coproporphyrin were raised. The erythrocytic porphyrins showed a level of 124.3 μg/100 ml (reference value less than 40 μg/100 ml using the hematofluorometric method). A diagnosis of CEP was made.

Discussion

Porphyrias are caused by partial deficiency of enzymes required for haem synthesis. Haem is synthesized from glycine and succinyl CoA via an eight-step pathway, with each step being catalysed by a separate enzyme [Table 1]. Accumulation of PBG leads to acute attacks. Accumulation of products of subsequent reactions do not lead to acute attacks but, instead, cause photosensitivity.

Table 1

Haem biosynthetic pathway showing the sites of enzyme deficiencies in the different porphyrias

Clinically, porphyrias are classified as 1) acute attacks (neuropsychiatric) only, e.g., acute intermittent porphyria (AIP) and ALA dehydratase deficiency; 2) cutaneous (photosensitivity), e.g., porphyria cutanea tarda (PCT), congenital erythropoietic porphyria (CEP), and erythropoietic protoporphyria (EPP); 3) both cutaneous disease and acute attacks, e.g., variegate porphyria (VP) and hereditary coproporphyria (HCP). Blisters are the presenting features of PCT, CEP, VP, and HCP, and these constitute the bullous porphyrias. The common features of bullous porphyrias are vesicobullous lesions on photo-exposed parts, hypertrichosis, atrophic scars, hyperpigmentation, milia, and scleroderma-like lesions.

Porphyrins absorb photons (light) of around 408 nm wave length,[1] get excited, and move to higher orbital levels in molecules. The excited electrons return to their normal positions by transferring energy to surrounding structures, thus causing damage. Porphyrins cannot cause tissue damage unless they absorb the energy of sunlight. Hence damage is seen mostly in sun-exposed areas.

The bulla in porphyria is subepidermal, with dermal papillae festooning into the floor. Periodine acid schiff (PAS)-positive and diastase-resistant hyaline material is found in the perivascular areas. Direct immunofluorescence reveals deposits of IgG (less commonly, IgM and complement) in and around the upper dermal vessels and at the dermoepidermal junction.

In most of the other photodermatoses inflammation is usually not severe enough to produce blisters. This severe phototoxicity of porphyrins is used to therapeutic advantage in photodynamic therapy, where porphyrin precursors like aminolevulinic acid or ALA (which gets converted to porphyrins) is used to cause destruction of tumor and diseased cells. Porphyrins chelated with metals like iron, zinc, and cobalt do not show phototoxicity.[2]

CEP is extremely rare and till recent times less than 200 cases have been reported in world literature.[3] CEP is due to deficiency of the enzyme uroporphyrinogen III cosynthase (UIIIC). The mutation that causes the most severe deficiency of the enzyme uroporphyrinogen III synthase is C73R. It results in an increase in uroporphyrin I and coproporphyrin I in plasma, red blood cells, urine, feces, and in different tissues.

The clinical spectrum of CEP is highly variable and ranges from nonimmune hydrops fetalis as a result of severe hemolytic anemia in utero to late-onset mild cases where the only symptoms are cutaneous lesions in the adult. The presence of large amounts of porphyrins in CEP very early in life, at the time of teeth and bone development, results in erythrodontia due to deposition of porphyrins in the developing teeth. This is almost pathognomonic of CEP.[2] The photoactive nature of porphyrin molecules results in the bright pink fluorescence of these pigments in urine, teeth, and bones under Wood's lamp illumination. Hemolytic anemia can be mild or severe and may result in gallstones, splenomegaly, osseous fragility, and compression fractures. Hypertrichosis may often lead to what is sometimes called the “werewolf syndrome.” Phototoxicity is characteristically very severe, leading to the formation of blisters and recurrent atrophic scars that result in characteristic mutilation of fingers.

Epidermolysis bullosa forms a close differential diagnosis due to presence of blistering, scarring, and mutilation. Pseudoporphyria is a drug-induced bullous photosensitive disorder and mimics porphyria very closely. However, in pseudoporphyria, the porphyrin levels in urine, plasma, and stools are not increased. CEP may mimic hepatoerythropoietic porphyria, the rare homozygous form of PCT.

A diagnosis of porphyria can only be made if there is a high index of suspicion in all cases of photosensitivity, abdominal pain, and unexplained seizures. Confirmation of the diagnosis of cutaneous porphyria can be made by initial screening of the total porphyrin with a spectrophotometer (semi-quantitation of porphyrins can be achieved by scanning acidified urine or fecal extracts between 350 nm and 450 nm) or a spectrofluorometer. The specimens analysed are urine and plasma (if a spectrofluorometer is available) or feces (if a spectrofluorometer is not available). The spectrofluorometer is a better instrument as it gives specific curves for VP and EPP.[4] Next, exact typing of porphyrias can be done with high-pressure liquid chromatography (HPLC) by identifying the accumulated porphyrins. It is particularly important to distinguish between PCT and acute porphyrias like VP and HC which may also present with skin lesions alone. This latter group of patients are at risk of developing life-threatening acute attacks on exposure to the precipitating factors.

CEP has severe presentation in early childhood and its management is very critical. The only available prophylactic measure for CEP is total avoidance of sun light.[5] Therapeutic interventions include β-carotene to decrease oxidative damage, splenectomy to reduce anemia and thrombocytopenia, transfusion regimens, and intravenous hematin (oxidized free heem) therapy to suppress hemoglobin production by a negative feedback mechanism, adsorbents to bind to porphyrins and increase their excretion, hydroxyurea, and corticosteroids.

Bone marrow transplantation is reported to be successful as it substitutes the erythroblasts of the medulla and produces normal levels of UIIIC and reverse the disease manifestations. But life-threatening infectious complications limit the application of this approach.[67] Stem cell transplantation is currently the only known curative therapy and has been successful in a few patients.

There are few reports of CEP in Indian literature.[8-12] The paucity of reports of congenital erythropoietic porphyria in the world literature has prompted us to report these two classical cases.